Infection with Leishmania causes significant morbidity and mortality worldwide. The type of Leishmania species infecting the host and the immune response generated by the host determines the spectrum of clinical disease that is seen. In particular, the pattern of cytokine production from T cells is critical for protection. At present there is no vaccine for Leishmania that is easy to administer, efficacious, and cost effective. These experiments will seek to establish a vaccine regimen that is sufficient to confer long-term protective immunity following infectious challenge in mice and primates. Experiments will specifically focus on DNA, protein and recombinant viral vaccines. In addition, these studies will evaluate the cellular and molecular mechanisms by which different vaccine formulations induce long-term protective cellular immunity. Over the past year we have determined the following. 1. IL-10 influences the magnitude and quality of Th1 responses following protein+ CpG immunization. 2. Adenovirus Type 5 immunization encoding a leishmanial antigen induces a high frequency of IL-10 producing CD4+ T cells with or without IFN-g. 3. IL-10 produced by CD4+ T cells following rAd-5 immunization does not improve protection by Th1 responses generated by the vaccine. 4. Antigen dose and the amount of TLR adjuvant (CpG) influence the magnitude and quality of Th1 responses.